Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol

Abstract

The therapeutic potential of tocotrienol, a member of the vitamin E family of compounds with potent in vitro anti-cancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study is to determine whether a novel tumor-targeted vesicular formulation of tocotrienol would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo.In this work, we demonstrated that novel transferrin-bearing multilamellar vesicles entrapping -T3 resulted in a dramatically improved (by at least 52-fold) therapeutic efficacy in vitro on A431 cell line, compared to the free drug. In addition, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles resulted in tumor suppression for 30% of A431 and 60% of B16-F10 tumors, without visible toxicity. Mouse survival was enhanced by more than 13 days compared to controls administered with the drug solution only. This tumor-targeted, tocotrienol-based nanomedicine therefore significantly improved the therapeutic response in cancer treatment. KEYWORDSTocotrienol; transferrin; tumor targeting; delivery system; cancer therapy 2 1. Introduction Tocotrienol, a member of the vitamin E family of compounds, is currently receiving increased attention because of its promising anti-tumor activity [1,2]. It has been reported to exert its anti-cancer effects through various mechanisms, such as activation of p53, modulation of Bax/Bcl-2 ratio, decrease of oxidative stress and induction of apoptosis [1][2][3][4]. It can also inhibit angiogenesis by downregulating the expression of the vascular endothelial growth factor (VEGF) receptor and blocking intracellular VEGF signaling. In addition, it is able to potentiate apoptosis through inhibition of DNA polymerase and telomerase and of NF-B activation pathway [1][2][3][4]. This wide range of anti-cancer effects therefore makes tocotrienol a very promising therapeutic molecule. However, its efficacy against cancer cells in vivo is hindered by its inability to specifically reach cancer cells at a therapeutic concentration, without affecting normal cells. Given its anti-proliferative properties, it is of the utmost importance to find a strategy to deliver this therapeutic drug specifically to its site of action. On the basis that iron is essential for tumor cell growth and can be effectively carried to tumors by using transferrin receptors overexpressed on cancer cells [5,6], we recently demonstrated that the conjugation of transferrin (Tf) to vesicles entrapping tocotrienol-rich fraction (TRF) extracted from palm oil could lead to tumor regression, and even tumor suppression, on both the tested cancer cell lines, following intravenous injection to a murine model [7][8][9]. It resulted in complete tumor eradication for 50% of B16-F10 tumors and 20% of A431 tumors [7]. The treatments were well tolerated by the animals, without weight loss or apparent signs of toxicity. These previous studies, however, used TRF but did not ev...

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